Vgamma2Vdelta2 T cells comprise 2%-5% of human peripheral blood T cells, recognize ubiquitous nonpeptide antigens, and expand up to 50-fold during microbial infection. It is not clear why these Vgamma2Vdelta2 T cells expand only after microbial infection. We show here that the stress-inducible molecule, MICA, is induced on the surface of dendritic and epithelial cells by infection with M. tuberculosis in vitro and in vivo. MICA engagement by the activating receptor, NKG2D, present on Vgamma2Vdelta2 T cells, resulted in a substantial enhancement of the TCR-dependent Vgamma2Vdelta2 T cell response to nonpeptide antigens and protein superantigens alike. Thus, a MICA-NKG2D interaction may be necessary for an effective innate immune response to microbe-associated antigens that also are constitutively present in vivo.